Atherosclerosis, the process of vascular wall thickening and hardening, is a significant contributing factor in the development of cardiovascular disease (the leading cause of morbidity and mortality in the U.S.). Therefore, understanding the molecular mechanisms involved in atherosclerotic lesion (atheroma) progression has significant relevance in human disease and therapeutic development. We recently identified a novel role for the endocytic adaptor protein, epsin, as a pro-atherogenic and pro-inflammatory regulator in the endothelium. Specifically, we observed that epsins 1 and 2 are upregulated in the aortic atheroma of western diet fed ApoE-/- mice. Furthermore, we found that epsin-depletion in macrophages protects against atherosclerosis in part by impairing lipoprotein accumulation and foam cell development. This phenotype is in direct contrast to that of LRP-1-deficient mice suggesting a link between epsin function and LRP-1 regulation, which has never before been investigated. Therefore, in this proposal we describe a research strategy to test the central hypothesis that epsins interact with and facilitate the internalization of LRP-1, thus impairing efferocytosis and contributing to foam cell maturation and atheroma development. In support, we report that epsin deficiency is associated with increased total and cell surface LRP-1 expression in macrophages in vitro. Furthermore, we have preliminary data suggesting that epsin 1 and LRP-1 interact in vitro. Therefore, we propose a research strategy to characterize the molecular mechanisms by which epsins interact with LRP-1 in macrophages and to determine if this interaction results in the downregulation of LRP-1 resulting in impaired efferocytosis and atheroma development. In summary, the information gained from this proposal will provide a novel regulator, and potential new therapeutic target, for the development and progression of atherosclerosis.